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Research into pulmonary arterial hypertension

Genetics could hold the key to understanding a debilitating heart and lung condition. Professor Nick Morrell talks to Sarah Kidner about how his life-saving work could one day help people like Kath Graham.

Until September 2013, Kath Graham, 52, spent much of her time in a wheelchair as a result of her pulmonary arterial hypertension (PAH). PAH is a chronic and debilitating condition that affects the blood vessels in the lungs, leading to heart failure, and leaves sufferers feeling breathless and tired.

When Kath, from Hertfordshire, was diagnosed four years ago, doctors told her she was in the ‘end stage’, meaning they expected her to die of the condition soon.

Permanent medication

Kath needed to have continuous intravenous (IV) medications. “It meant I carried around a small pump on an elastic waistband,” she explains. “I had to prepare an infusion in a sterile environment twice a day and put that into a syringe attached to the pump, which then infused the drug continuously through a permanent line fitted by the hospital.

“I didn’t have a choice at that stage. Just climbing out of bed, I would pass out, so I had a sort of love/hate relationship with the medication. I knew the IV drugs were helping to keep me going until I could get a transplant, but they also made me feel nauseous.”

Kath says the medications, designed to widen the blood vessels, also made her skin red and blotchy, though not everyone experiences side effects.

Severe forms of PAH like Kath’s are, thankfully, rare, although PAH is more common in women.

I knew the IV drugs were keeping me going until I could get a transplant, but they also made me feel nauseous

Professor Nick Morrell, Chair of Cardiopulmonary Medicine at Cambridge University, explains: “PAH affects at least twice as many women as men. These women are typically in their 30s or 40s. PAH occurs unexpectedly and, tragically, often around the time of childbirth.

It is thought that pregnancy may be a trigger for the disease in someone who is genetically susceptible, or that the additional blood flow required to supply the baby gives rise to symptoms earlier than if the person had not been pregnant. However, it can affect people at any stage of life.”

When Kath was 33 she gave birth to her second daughter Rose. Soon after, she began to have regular fainting episodes. At the time, Kath’s GP referred her for tests, but they didn’t detect any abnormalities.

Over the next 15 years, Kath continued to have dizzy spells and then, aged 49, says she’d fainted “three or four times” in a week and had swelling in her ankles.

“When they did a heart echo, they saw the right-hand side of my heart was enlarged. An angiogram showed that there was a lot of pressure in my lungs and the cardiologist recognised it as PAH.”

In the genes?

Pulmonary hypertension is a common complication of heart failure but much more rarely occurs spontaneously in people who don’t have any other known cause of the disease, when it is known as pulmonary arterial hypertension (PAH). This spontaneous or idiopathic form of the disease affects about 6,500 people in the UK.

Pulmonary hypertension as a complication of heart failure is usually less severe.

Kath is one of the 6,500 suffering from PAH. Cases such as hers can be hard to diagnose. In about 20 per cent of those who have idiopathic PAH, the cause may be genetic.

Identifying these people is the focus of Professor Morrell’s work. He says: “We know that, if you have one or more family members affected by idiopathic PAH, 70 per cent of the time you’ll have a mutation of one particular gene called BMPR-II [bone morphogenetic protein receptor type II].”

Professor Morrell and his team have funding from the BHF, including a £1.2m BHF Special Project Grant and a BHF/MRC Experimental Challenge Grant of £3.2m.

“This means that, over the next three years, we hope to be able to establish the frequency of all the known genetic mutations and identify new mutations that alongside BMPR-II are responsible for causing the condition,” he explains.

The hope is that it may be possible to introduce a screening programme that can identify those at risk, provide better information to families and identify new ways to treat the disease.

Kath has been screened and doesn’t have any of the genes commonly associated with PAH, she says. “I was tested at Addenbrooke’s Hospital for the two most common genes identified with inherited idiopathic PAH and when the results came through last year, it was a huge relief to be told that no genetic misprints were found, making it very unlikely that it would be passed on to our two daughters.

When the results came through last year, it was a huge relief to be told that no genetic misprints were found

“Up until then, there was always the nagging doubt that they might fall prey to the condition, but this gave us tremendous reassurance it’s now extremely unlikely.”

Alternative treatments

Professor Morrell has also discovered that in people who have other, non-genetic causes of PAH, such as lung disease and heart failure, the same pathway that controls BMPR-II is also not working correctly. “If we can piece together what causes this disease in other settings then it helps our understanding of how PAH occurs and we can suggest possible cures,” he says.

One of these potential treatments is a drug called chloroquine, traditionally used for the treatment of malaria, and which, Professor Morrell says, “corrects some of the mutations in this gene”.

However, running clinical trials isn’t easy. “I work at Papworth Hospital, one of the national centres for people with severe PAH. It reminds you that transferring things from the lab to the clinic is a big step. I could identify ten things I think might improve the outlook of people suffering from PAH, but you have to make highly informed choices because it can take years to complete a clinical trial in this rare disease and you don’t want to give people false hope.”

After two years on the waiting list, Kath received a heart and lung transplant in September 2013, and is now out of her wheelchair and able to walk about three miles.

Centres of Research Excellence

Total funding to date awarded by the BHF and areas of special interest

£11.9m Imperial College: World-leading stem cell researcher BHF Professor Michael Schneider and his team hope to come up with ways to reverse the damage caused by heart failure. Read about the work of an Imperial PhD student in this field.

£15m King’s College London: This centre is making great strides in understanding the structure of the heart at a molecular level. One of our newest BHF Professors, Kinya Otsu from Japan, is researching new treatments for heart failure.

£3m University of Cambridge: BHF Professor Nick Morrell (pictured above) and his team are using innovative research approaches to find ways to prevent heart attacks.

Fight for every heartbeat

British Heart Foundation is a registered Charity No. 225971. Registered as a Company limited by guarantee in England & Wales No. 699547. Registered office at Greater London House, 180 Hampstead Road, London NW1 7AW. Registered as a Charity in Scotland No. SC039426

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